OP0136 METABOLOMIC SERUM PROFILING IDENTIFIES METABOLITES LINKED TO KIDNEY DAMAGE WHICH ARE MODULATED BY ANIFROLUMAB IN A PHASE 2 TRIAL IN LUPUS NEPHRITIS
Authors: D. Jayne, P. Gavin, E. Allman, C. Di Poto, X. Tian, S. Hess, M. Ramaswamy, M. Lazarus, P. Z. Brohawn, D. Muthas, A. Platt, H. Al-Mossawi, C. Lindholm, N. Ferrari
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Lupus nephritis (LN) is one of the most common severe clinical manifestations of systemic lupus erythematosus (SLE), occurring in 21%–48% of SLE patients.<sup>[1]</sup> The kidney is the major organ affected in SLE, with persistent inflammation leading to progressive loss of renal function and chronic kidney disease (CKD). The decline in kidney function leads to an accumulation of metabolic waste products normally cleared by the kidneys, known as uremic toxins. Uremic toxins negatively affect multiple organ systems, causing increased cardiovascular and kidney damage, among other effects.<sup>[2]</sup> Given the clear link to kidney function, uremic toxins may serve as biomarkers of kidney damage and of treatment response. Anifrolumab, a monoclonal antibody that targets the type I interferon (IFN) receptor subunit 1, is approved for moderate to severe SLE treatment<sup>[3]</sup> and intensified dosing is being evaluated in a phase 3 study for LN treatment. <h3>Objectives</h3> In this study, we conducted unbiased metabolomic serum profiling to identify novel biomarkers of treatment response and provide insights into the mechanism of action of anifrolumab in LN. <h3>Methods</h3> In the 52-week phase 2 clinical trial TULIP-LN (NCT02547922), 147 patients with active LN were randomized 1:1:1 to receive intravenous anifrolumab every 4 weeks at standard SLE dosing (basic regimen [BR], 300 mg), intensified dosing (intensified regimen [IR], 900 mg for the first 3 doses, 300 mg thereafter), or placebo in addition to standard therapy.<sup>[4]</sup> Serum samples were obtained from 140 of these patients at baseline (BL) and Weeks 12, 24, and 52. Serum metabolites were analyzed using an unbiased liquid chromatography–mass spectrometry-based approach. Metabolites that were differentially modulated in the anifrolumab IR vs placebo group were identified using a mixed effects model evaluating the interaction of metabolite levels and treatment, adjusted for patients' IFN gene signature (IFNGS) status (high/low) and 24-hour urine protein–creatinine ratio (UPCR &gt;3 or ≤3). Relationships between BL metabolite level and clinical characteristics of kidney damage were assessed by Spearman's correlation. Association of BL metabolite levels with complete renal response were evaluated by logistic regression, adjusted for IFNGS and UPCR status. <h3>Results</h3> Our unbiased metabolomic approach identified 2 metabolites significantly impacted by anifrolumab treatment compared with placebo (Figure 1). Cytosine (Cyt) and indoxyl sulfate (IS) levels were significantly reduced following anifrolumab IR treatment compared with placebo, while an intermediate, non-significant reduction was observed longitudinally with anifrolumab BR. At baseline, Cyt and IS serum levels were positively correlated with serum creatinine and negatively correlated with estimated glomerular filtration rate. Baseline IS levels were also associated with complete renal response at Week 52. Compared to the trend observed in nonresponders, IS levels in responders were reduced from BL to Week 52. A trend in reduction of multiple uremic toxins not limited to IS was detected in the anifrolumab-treated group. <h3>Conclusion</h3> In patients with LN, anifrolumab treatment reduced levels of multiple circulating uremic toxins including IS, a known inducer of cardiovascular damage in CKD.<sup>[5]</sup> Together, correlations with kidney damage measures at baseline and reductions in IS levels in responders vs nonresponders at Week 52 suggest improvements in kidney function following anifrolumab treatment. Overall, our results contribute to a deeper understanding of how inhibition of type I IFN affects renal disease in LN. <h3>References</h3> [1] Wang H, et al. <i>Arch Rheumatol.</i> 2017;33:17–25. [2] Rosner MH, et al. <i>Clin J Am Soc Nephrol.</i> 2021;16:1918–28. [3] AstraZeneca. Saphnelo prescribing information. 2021. [4] Jayne D, et al. <i>Ann Rheum Dis.</i> 2022;81:496–506. [5] Zoccali C, et al. <i>Nat Rev Nephrol.</i> 2017;13:344–58. <h3>Acknowledgements</h3> Writing assistance by Katey Glunt, PhD, of JK Associates Inc., part of Fishawack Health. This study was sponsored by AstraZeneca. <h3>Disclosure of Interests</h3> David Jayne Shareholder of: Aurinia, Speakers bureau: GSK, CSL Vifor, Consultant of: AstraZeneca, Chemocentryx, CSL Vifor, GSK, Novartis, Roche, Takeda, Grant/research support from: GSK, Roche, Patrick Gavin Employee of: AstraZeneca, Erik Allman Shareholder of: Primarily AstraZeneca but others through various Exchange Traded Funds (ETFs), Employee of: Previously, Janssen/Johnson &amp; Johnson. Currently, AstraZeneca, Cristina Di Poto Shareholder of: AstraZeneca, Employee of: AstraZeneca, Xiang Tian Shareholder of: AstraZeneca, Employee of: AstraZeneca, Sonja Hess Shareholder of: AstraZeneca, Employee of: AstraZeneca, Madhu Ramaswamy Shareholder of: GSK, Employee of: AstraZeneca (until Jan 2023), GSK (from Jan 2023), Mark Lazarus Consultant of: Paid consulting for Novartis and Sandoz over 2 years ago, Employee of: AstraZeneca, Philip Z Brohawn Shareholder of: AstraZeneca, Employee of: AstraZeneca, Daniel Muthas Shareholder of: AstraZeneca, Employee of: AstraZeneca, Adam Platt Shareholder of: AstraZeneca, Employee of: AstraZeneca, Hussein Al-Mossawi Shareholder of: AstraZeneca, UCB, GSK, Speakers bureau: Novartis, Pfizer, UCB, Consultant of: Novartis, UCB, AbbVie, Grant/research support from: UCB, Employee of: UCB (Previous), AstraZeneca (Current), Catharina Lindholm Shareholder of: AstraZeneca, Employee of: AstraZeneca, Nicola Ferrari Shareholder of: AstraZeneca, Employee of: AstraZeneca.